EP0968206B8 - Derives n-heterocycliques utiles en tant qu'inhibiteurs de la no synthetase - Google Patents

Derives n-heterocycliques utiles en tant qu'inhibiteurs de la no synthetase Download PDF

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Publication number
EP0968206B8
EP0968206B8 EP98906555A EP98906555A EP0968206B8 EP 0968206 B8 EP0968206 B8 EP 0968206B8 EP 98906555 A EP98906555 A EP 98906555A EP 98906555 A EP98906555 A EP 98906555A EP 0968206 B8 EP0968206 B8 EP 0968206B8
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Prior art keywords
imidazol
acetamide
methyl
piperazine
pyrimidin
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EP98906555A
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English (en)
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EP0968206B1 (fr
EP0968206A1 (fr
Inventor
Damian O. Arnaiz
John J. Baldwin
David D. Davey
James J. Devlin
Roland Ellwood Dolle, Iii
Shawn David Erickson
Kirk Mcmillan
Michael M. Morrissey
Michael H. J. Ohlmeyer
Gonghua Pan
Vidyadhar Madhav Paradkar
John Parkinson
Gary B. Phillips
Bin Ye
Zuchun Zhao
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3000 Eastpark Boulevard Cranbury New Jersey 0851
Pharmacopeia Drug Discovery Inc
Bayer Healthcare Pharmaceuticals Inc
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Pharmacopeia Inc
Berlex Inc
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Priority to EP06023449A priority Critical patent/EP1754703A3/fr
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
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    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the invention relates to a series of ⁇ /-heterocyclic compounds and derivatives useful as inhibitors of nitric oxide synthase (NOS) and to methods of therapy for various diseases employing those compounds.
  • NOS nitric oxide synthase
  • Nitric oxide is produced under various conditions by virtually all nucleated mammalian cells. A number of pathologies are ascribed to abnormalities in NO production including stroke, insulin dependent diabetes, septic shock-induced hypotension, rheumatoid arthritis and multiple sclerosis. Nitric oxide is synthesized in biological tissues by an enzyme called nitric oxide synthase (NOS) which uses NADPH and molecular oxygen to oxidize L-arginine to citrulline and nitric oxide.
  • NOS nitric oxide synthase
  • Nitric oxide synthase exists in at least three isoforms, which fall into two primary categories: constitutive and inducible. Two constitutive isoforms, which are calcium and calmodulin dependent, have been identified, and one inducible isoform has been identified.
  • the constitutive isoforms are (1 ) a neuronal isoform, NOS-1 or nNOS, which is found in the brain and skeletal muscles and (2) an endothelial isoform, NOS-3 or eNOS, which is expressed in the endothelium of blood vessels, the epithelium of the bronchial tree and in the brain. These constitutive isoforms are not the target of the NOS inhibitors of the present invention.
  • the inducible isoform (NOS2 or iNOS) is expressed in virtually all nucleated mammalian cells following exposure to inflammatory cytokines or lipopolysaccharide. Its presence in macrophages and lung epithelial cells is particularly noteworthy.
  • the inducible isoform is neither stimulated by calcium nor blocked by calmodulin antagonists. It contains several tightly bound co-factors, including FMN, FAD and tetrahydrobiopterin.
  • Nitric oxide generated by the inducible form of NOS has been implicated in the pathogenesis of inflammatory diseases.
  • hypotension induced by lipopolysaccharide or tumor necrosis factor ⁇ can be reversed by NOS inhibitors.
  • Conditions which lead to cytokine-induced hypotension include septic shock, hemodialysis and interleukin therapy in cancer patients. It is expected that an iNOS inhibitor would be effective in treating cytokine-induced hypotension.
  • NOS inhibitors would therefore have beneficial effects on inflammatory bowel disease, cerebral ischemia and arthritis.
  • Inhibitors of NOS may also be useful in treating adult respiratory distress syndrome (ARDS) and myocarditis, and they may be useful as adjuvants to short term immunosuppression in transplant therapy.
  • ARDS adult respiratory distress syndrome
  • myocarditis myocarditis
  • the invention is directed to compounds of formula (I), formula (II) and formula (III):
  • A is -R 1 , -OR 1 , -C(O)N(R 1 )R 2 , -P(O)[N(R 1 )R 2 ] 2 , -N(R 1 )C(O)R 2 , -N(R 16 )C(O)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(O)N(R 1 )R 16 , -S(O) t R 1 , -SO 2 NHC(O)R 1 , -NHSO 2 R 22 , -S0 2 N(R 1 )H,
  • each X, Y and Z are independently N or C(R 19 ); each U is N or C(R 5 ), provided that U is N only when X is N and Z and Y are CR 19 ;
  • V is N(R 4 ), S, O or C(R 4 )H; each W is N or CH;
  • -S(0) t R 1 (where t is zero), or -NHS0 2 R 22 , n, q, and r cannot all be zero; and when Q is a heteroatom and A is -OR 1 , -N(R 1 )C(0)R 2 , -N(R 16 )C(0)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(O)N(R 1 )R 16 , -S(O) t R 1 (when t is zero) or -NHSOzR 22 , m and n cannot both be zero; t is zero, one or two;
  • each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C C 2 o alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[C C 8 ]-R 11 (optionally substituted by hydroxy), optionally substituted heterocyclyl; or R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl; R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyl, -[
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(O),-R 16 , -N(R 16 )R 21 , -N(R 16 )C(0)N(R )R 16 ,
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, alkyl]-R 8 ,
  • each R 8 and R 9 are independently chosen from the group consisting of haloalkyi, cycloalkyi
  • each R 10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted -S(0) t -R 22 , acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, alkylsulfonamido; each R 11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl; each R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R , R ,
  • the invention is directed to compounds of formula (IV):
  • AA is an amino acid
  • X, Y and Z are independently N or C(R 19 );
  • U is N or C(R 5 ), provided that U is N only when X is N and Z and Y are CR 19 ; W is N or CH;
  • R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C r C 20 alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 ,
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(0) t -R 16 , -N(R 6 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -N(R 16 )C(O)OR 16 , -N(R 16 )C(O)R 16 , -
  • each R 9 is independently chosen from the group consisting of haloalkyi, cycloalkyi (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy); each R 10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted -S(0) t -R 22 , acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amin
  • each R 22 is independently alkyl, cycloalkyi, optionally substituted aryl or optionally substituted aralkyl; and t is zero, one or two; as a single isomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to compounds of formula (Va), formula (Vb) or formula (Vc):
  • B is a fused 5-or 6-membered optionally substituted carbocyclyl or heterocyclyl; and wherein:
  • A is -R 1 , -OR 1 , -C(O)N(R 1 )R 2 , -P(0)[N(R 1 )R 2 ] 2 , -N(R 1 )C(0)R 2 , -N(R 16 )C(O)OR 2 , -N(R 1 )R 21 ,
  • each X and Y are independently N or C(R 19 ); V is N(R 4 ), S, O or C(R 4 )H; each W is N or CH;
  • each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C 1 -C 2 o alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[C C 8 ]-R 11 (optionally substituted by hydroxy), optionally substituted heterocyclyl; or R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl; R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, halo
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C ⁇ C 8 alkyl]-R 8 ,
  • each R 8 and R 9 are independently chosen from the group consisting of haloalkyi, cycloalkyi
  • each R 10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted -S(0) r R 22 , acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy, mercapto, alkylsulfonamido; each R 11 is independently chosen from the group consisting of cyano, di(alkoxy)alkyl, carboxy, alkoxycarbonyl, aminocarbonyl, monoalkylaminocarbonyl and dialkylaminocarbonyl; each R 12 , R 13
  • R 18 is hydrogen, NO 2 , or toluenesulfonyl; each R 19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyi; each R 21 is independently hydrogen, alkyl, cycloalkyi, optionally substituted aryl, optionally substituted aralkyl, -C(O)R 22 or -SO 2 R 22 ; or R 21 taken together with R 1 and the nitrogen to which they are attached is an optionally substituted ⁇ /-heterocyclyl; or R 21 taken together with R 16 and the nitrogen to which they are attached is an optionally substituted ⁇ /-heterocyclyl; each R 22 is independently alkyl, cycloalkyi, optionally substituted aryl or optionally substituted aralkyl; and R 23 is an amino acid residue; as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a compound of formula (Via), formula (Vlb) or formula (Vic):
  • B is a fused 5-or 6-membered optionally substituted carbocyclyl or heterocyclyl; and wherein:
  • A is -R 1 , -OR 1 , -C(O)N(R 1 )R 2 , -P(O)[N(R 1 )R 2 ] 2 , -N(R 1 )C(O)R 2 , -N(R 16 )C(0)OR 2 , -N(R 1 )R 21 ,
  • each X and Z are independently N or C(R 19 ); V is N(R 4 ), S, O or C(R 4 )H; each W is N or CH;
  • each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C C 2 o alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[C C 8 ]-R 11 (optionally substituted by hydroxy), optionally substituted heterocyclyl; or R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl; R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyi, -[
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C C 8 alkyl]-R 8 ,
  • each R 8 and R 9 are independently chosen from the group consisting of haloalkyi, cycloalkyi
  • R 18 is h nyyddrogen, NO 2 , or toluenesulfonyl; each R 19 is independently hydrogen, alkyl (optionally substituted with hydroxy), cyclopropyl, halo or haloalkyi; each R 21 is independently hydrogen, alkyl, cycloalkyi, optionally substituted aryl, optionally substituted aralkyl, -C(O)R 22 or -SO 2 R 22 ; or R 21 taken together with R and the nitrogen to which they are attached is an optionally substituted ⁇ /-heterocyclyl; or R 21 taken together with R 16 and the nitrogen to which they are attached is an optionally substituted ⁇ /-heterocyclyl; each R 22 is independently alkyl, cycloalkyi, optionally substituted aryl or optionally substituted aralkyl; and R 23 is an amino acid residue; as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to compounds of formula (Vila), formula (Vllb) or formula (Vile):
  • A is -R 1 , -OR 1 , -C(O)N(R 1 )R 2 , -P(0)[N(R 1 )R 2 ] 2 , -N(R 1 )C(0)R 2 , -N(R 16 )C(O)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(O)N(R 1 )R 16 , -S(O) t R 1 , -S0 2 NHC(O)R 1 , -NHS0 2 R 22 , -SO 2 N(R 1 )H,
  • each X, Y and Z are independently N or C(R 19 ); each U is N or C(R 5 ), provided that U is N only when X is N and Z and Y are CR 19 ; V is N(R 4 ), S, O or C(R 4 )H; each W is N or CH;
  • each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C 1 -C 2 o alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[CrC 8 ]-R 11 (optionally substituted by hydroxy), optionally substituted heterocyclyl; or R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl; R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyi
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(0) r R 16 , -N(R 16 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -N(R 16 )C(O)OR 16 , -N(R 16 )C(0)R 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[C 0 -C 8 alkyl]-C(H)[C(0)OR 16 ] 2 , and -[C 0 -C 8 alkyl]-C(0)N(R 1 )R 16 ;
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C C 8 al
  • the invention is directed to compounds of formula (IXa), formula (IXb) or formula (IXc):
  • each X, Y and Z are independently N or C(R 19 ⁇ ); each U is N or C(R 5 ), provided that U is N only when X is N and Z and Y are CR 19 ;
  • V is N(R 4 ), S, O or C(R 4 )H; each W is N or CH;
  • -S(O) t R 1 (where t is zero), or -NHS0 2 R 22 , n, q, and r cannot all be zero; and when Q is a heteroatom and A is -OR 1 , -N(R )C(0)R 2 , -N(R 16 )C(0)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(O)N(R 1 )R 16 , -S(O) t R 1 (when t is zero) or -NHSO 2 R 22 , m and n cannot both be zero; t is zero, one or two;
  • each R 2 is independently chosen from the group consisting of hydrogen, optionally substituted C C 20 alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[C C 8 ]-R 11
  • R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyi, -[C C ⁇ alkyl]-C(0)N(R 1 )R 2 , -[C r C 8 alkyl]-N(R 1 )R 2 , -[C C 8 alkyl]-R 8 , -[C 2 -C 8 alkyl]-R 10 , -[Ci-C ⁇ alkyl]-R 11 , and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of halo, alkyl, alkoxy and imidazolyl); or when Q is -N(R 6 )- or a direct bond to R 3 , R 3 may additionally be aminocarbonyl, alkoxycarbonyl, alkylsulfonyl, monoalkylaminocarbonyl,
  • R is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(0) t -R 16 , -N(R 16 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -N(R 16 )C(O)OR 16 , -N(R 16 )C(0)R 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[Co-C ⁇ alkyl]-C(H)[C(0)OR 16 ] 2 , and -[C 0 -C 8 al
  • each R 8 and R 9 are independently chosen from the group consisting of haloalkyi, cycloalkyi (optionally substituted with halo, cyano, alkyl or alkoxy), carbocyclyl (optionally substituted with one or more substituents selected from the group consisting of halo, alkyl and alkoxy), and heterocyclyl (optionally substituted with alkyl, aralkyl or alkoxy); each R 10 is independently chosen from the group consisting of halo, alkoxy, optionally substituted aryloxy, optionally substituted aralkoxy, optionally substituted -S(0) t -R 22 , acylamino, amino, monoalkylamino, dialkylamino, (triphenylmethyl)amino, hydroxy,
  • R 23 is an amino acid residue; as a single stereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof.
  • the invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), formula (II) or formula (III) as described above and a pharmaceutically acceptable carrier.
  • the invention is directed to a process for synthesizing compounds of formula (I), formula (II) and formula (III):
  • A is -R 1 , -OR 1 , -C(O)N(R 1 )R 2 , -P(0)[N(R 1 )R 2 ] 2 , -N(R 1 )C(O)R 2 , -N(R 16 )C(O)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(O)N(R 1 )R 16 , -S(O) t R 1 , -S0 2 NHC(O)R 1 , -NHS0 2 R 22 , -S0 2 N(R 1 )H,
  • each X, Y and Z are independently N or C(R 19 ⁇ ); each U is N or C(R 5 ), provided that U is N only when X is N and Z and Y are CR 19 ;
  • V is N(R 4 ), S, or O; each W is N or CH;
  • -S(O) t R 1 (where t is zero), or -NHS0 2 R 22 , n, q, and r cannot all be zero; and when Q is a heteroatom and A is -OR 1 , -N(R 1 )C(0)R 2 , -N(R 16 )C(0)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(O)N(R 1 )R 16 , -S(O) t R 1 (when t is zero) or -NHS0 2 R 22 , m and n cannot both be zero; t is zero, one or two;
  • each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C C 20 alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[C r C 8 ]-R 11 (optionally substituted by hydroxy), optionally substituted heterocyclyl; or R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl; R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyi, -[
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(0) t -R 16 , -N(R 16 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -N(R 16 )C(O)OR 16 , -N(R 16 )C(O)R 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[C 0 -C 8 alkyl]
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C C 8 alkyl]-R 8 , -[C 2 -C 8 alkyl]-R 10 , -[C C 8 alkyl]-R 11 , acyl, -C(0)R 8 , -C(O)-[C r C 8 alkyl]-R 8 , alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted arylsulfonyl, aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, optionally substituted aryiaminocarbonyl, aminosulfonyl, monoalkylaminosulfonyl, dialky
  • U is N or C(R ), provided that U is N only when X is N and Z and Y are CR and provided that X, Y and Z can not all be C(R 19 ) when U is C(R 5 )
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(O),-R 16 , -N(R 16 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -N(R 6 )C(0)OR 16 ,
  • A is -R 1 , -OR 1 , -C(O)N(R 1 )R 2 , -P(0)[N(R 1 )R 2 ] 2 , -N(R 1 )C(0)R 2 , -N(R 16 )C(O)OR 2 , -N(R 1 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -S(O) t R 1 , -S0 2 NHC(0)R 1 , -NHS0 2 R 22 , -S0 2 N(R 1 )H,
  • V is N(R 4 ), S, or O;
  • each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C C 2 o alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 , -[C 2 -C 8 alkenyl]-R 9 , -[C 2 -C 8 alkynyl]-R 9 , -[C 2 -C 8 alkyl]-R 10 (optionally substituted by hydroxy), -[C C 8 ]-R 11 (optionally substituted by hydroxy), optionally substituted heterocyclyl; or R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl; R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyi, -[
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C C 8 alkyl]-R 8 , -[C 2 -C 8 alkyl]-R 10 , -[C C 8 alkyl]-R 11 , acyl, -C(O)R 8 , -C(OMC C 8 alkyl]-R 8 , alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocyclyl, alkoxycarbonylalkyl, carboxyalkyl, optionally substituted ary
  • A is -C(O)N(R 1a )R 2 ; each X, Y and Z are independently N or C(R 19 ); each U is N or C(R 5 ), provided that U is N only when X is N and Z and Y are CR 19 ; V is N(R 4 ), S, O or C(R 4 )H; each W is N or CH;
  • R 1a is hydrogen; each R 1 and R 2 are independently chosen from the group consisting of hydrogen, optionally substituted C ⁇ C ⁇ alkyl, optionally substituted cycloalkyi, -[C 0 -C 8 alkyl]-R 9 ,
  • R 1 and R 2 together with the nitrogen atom to which they are attached is an optionally substituted ⁇ /-heterocyclyl;
  • R 3 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, optionally substituted aryl, haloalkyi, -[C r C 8 alkyl]-C(0)N(R 1 )R 2 , -[C C ⁇ alkyl]-N(R 1 )R 2 , -[C r C 8 alkyl]-R 8 ,
  • R 4 is chosen from the group consisting of hydrogen, alkyl, aryl, aralkyl and cycloalkyi; provided that when A is -R 1 or -OR 1 , R 4 cannot be hydrogen, and when V is CH, R 4 may additionally be hydroxy;
  • R 5 is chosen from the group consisting of hydrogen, halo, alkyl, haloalkyi, optionally substituted aralkyl, optionally substituted aryl, -OR 16 , -S(0) t -R 16 , -N(R 16 )R 21 , -N(R 16 )C(0)N(R 1 )R 16 , -N(R 16 )C(O)OR 16 , -N(R 16 )C(0)R 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[C 0 -C 8 alkyl]-C(0)OR 16 , -[C 0 -C 8 alkyl]-C(H)[C(0)OR 16 ] 2 , and -[C 0 -C 8 alkyl]-C(0)N(R 1 )R 16 ;
  • R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C C
  • R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 17 , and R 20 are as defined above;
  • the invention is directed to a method of treating a condition resulting from an abnormality in nitric oxide production which comprises administering to a mammal having a condition resulting from an abnormality in nitric oxide production a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV), formula
  • Va formula (Vb), formula (Vc), formula (Via), formula (Vlb), formula (Vic), formula (Vila), formula (Vllb) or formula (Vile) as defined above.
  • Alkyl refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to eight carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, t?-propyl, 1-methylethyl (/so-propyl), n-butyl, n-pentyl, 1,1-dimethylethyl (f-butyl), and the like.
  • Alkyl radicals having more than eight carbon atoms are indicated herein by the notation "[C x -C y alkyl]" where x and y indicate the number of carbons present.
  • Alkyl radicals may be optionally substituted by one or more substituents independently selected from the group consisting of halo, hydroxy, alkoxy, carboxy, cyano, carbonyl, alkoxycarbonyl, cyano, amino, monoalkylamino, dialkylamino, nitro, alkylthio, amidino, aryl, heterocyclyl, aryloxy, aralkoxy, acylamino, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl.
  • Alkenyl refers to a straight or branched chain monovalent or divalent radical consisting solely of carbon and hydrogen, containing at least one double bond and having from one to eight carbon atoms, e.g., ethenyl, prop-1-enyl, but-1-enyl, pent-1-enyl, penta-1 ,4-dienyl, and the like.
  • Alkynyl refers to a straight or branched chain monovalent or divalent radical consisting solely of carbon and hydrogen, containing at least one triple bond and having from one to eight carbon atoms, e.g., ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-ynyl, pent-3-ynyl, and the like.
  • Alkoxy refers to a radical of the formula -OR a where R a is an alkyl radical as defined above, e.g., methoxy, ethoxy, propoxy, and the like.
  • Alkoxycarbonyl refers to a radical of the formula -C(O)OR a where R a is an alkyl radical as defined above, e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, and the like.
  • Alkoxycarbonylalkyl refers to a radical of the formula -R a -C(0)OR a where each R a is independently an alkyl radical as defined above, e.g., 2-(methoxycarbonyl)ethyl, 3-(ethoxycarbonyl)propyl, 4-(/?-propoxycarbonyl)butyl, and the like.
  • Alkylsulfonylamino refers to a radical of the formula -N(H)S(0) 2 -R a where R a is an alkyl radical as defined above, e.g., methylsulfonylamino, ethylsulfonylamino, and the like.
  • Alkylsulfonyl refers to a radical of the formula -S(O) 2 -R a where R a is an alkyl radical as defined above, e.g., methylsulfonyl, ethylsulfonyl, and the like.
  • Alkylthio refers to a radical of the formula -S-R a where R a is an alkyl radical as defined above, e.g., methylthio, ethylthio, n-propylthio, and the like.
  • Amino refers to a radical of the formula -C(NH)-NH 2 .
  • Amino refers to a radical of the formula -NH 2 .
  • Aminocarbonyl refers to a radical of the formula -C(O)NH 2 .
  • Aminosulfonyl refers to a radical of the formula -S(O) 2 NH 2 .
  • Aryl refers to a phenyl or naphthyl radical.
  • the aryl radical may be optionally substituted by one or more substituents selected from the group consisting of hydroxy, mereapto, halo, alkyl, alkenyl, alkynyl, phenyl, phenylalkyi, phenylalkenyl, alkoxy, phenoxy, phenylalkoxy, haloalkyi, haloalkoxy, formyl, nitro, cyano, cycloalkyi, hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amidino, ureido, alkoxycarbonyamino, amino, monoalkylamino, dialkylamino, monophenylamino, monophenylalkylamino, sulfonylamino, akylsulfonylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monophenyla
  • Alkyl refers to a radical of the formula -R a R b where R a is an alkyl radical as defined above and R is an aryl radical as defined above, e.g., benzyl, and the like.
  • the aryl radical may be optionally substituted as described above.
  • Aryloxy refers to a radical of the formula -OR b where R b is an aryl radical as defined above, e.g., phenoxy and naphthoxy, and the like.
  • the aryl radical may be optionally substituted as described above.
  • Aryloxycarbonyl refers to a radical of the formula -C(0)OR b where R b is an aryl radical as defined above, e.g., phenoxycarbonyl.
  • Alkoxy refers to a radical of the formula -OR c where R c is an aralkyl radical as defined above, e.g., benzyloxy, and the like.
  • R c is an aralkyl radical as defined above, e.g., benzyloxy, and the like.
  • the aralkyl radical may be optionally substituted as described above.
  • Alkoxycarbonyl refers to a radical of the formula -C(0)OR c where R c is an aralkyl radical as defined above, e.g., benzyloxycarbonyl, and the like.
  • the aralkyl radical may be optionally substituted as described above.
  • Arylaminocarbonyl refers to a radical of the formula -C(0)N(R b )H where R b is an aryl radical as defined above, e.g., phenylaminocarbonyl, and the like.
  • the aryl radical may be optionally substituted as described above.
  • Arylaminosulfonyl refers to a radical of the formula -S(O) 2 N(R b )H where R b is an aryl radical as defined above, e.g., phenylaminosulfonyl, and the like.
  • the aryl radical may be optionally substituted as described above.
  • Arylsulfonyl refers to a radical of the formula -S(O) 2 -R b where R b is an aryl radical as defined above, e.g., phenylsulfonyl, and the like.
  • the aryl radical may be optionally substituted as described above.
  • Arylsulfonylaminocarbonyl refers to a radical of the formula -C(0)N(H)S(0) 2 R b where R b is an aryl radical as defined above, e.g., phenylsulfonylaminocarbonyl, and the like.
  • the aryl radical may be optionally substituted as described above.
  • Acyl refers to a radical of the formula -C(O )-R a and -C(O)R b where R a is an alkyl radical as defined above and R is an aryl radical as defined above, e.g., acetyl, propionyl, benzoyl, and the like.
  • Acylamino refers to a radical of the formula -N(H)-C(0)-R a and -N(H)-C(0)-R b where
  • R a is an alkyl radical as defined above and R b is an aryl radical as defined above, e.g., acetylamino, benzoylamino and the like.
  • Alkylene refers to straight or branched chain divalent radical consisting solely of carbonl and hydrogen, containing no unsaturation and having from one to eight carbon atoms, e.g., methylene, ethylene, propylene, n-butylene, and the like.
  • the alkylene radical may be optionally substituted by one or more substituents selected from the group consisting of alkyl, hydroxy, -N(R 16 )R 21 or -C(O)N(R 1 )R 16 where R 1 , R 16 and R 21 are as defined above in the Summary of the Invention.
  • amino acid refers to a divalent radical of the formula -N(R 1 )-R 23 -C(O)- where R 1 is as described above in the Summary of the Invention for R 1 and R 23 is an amino acid residue.
  • Amino acid residue refers to the alkylene chain between the nitrogen atom and the carboxy group, which is substituted by the various "side chains" of the known amino acids.
  • amino acid residues of c -amino acids include the ⁇ -carbon (to which the carboxy group and the nitrogen atom is attached) and the side chain.
  • the amino acid residue of alanine is -C(CH 3 )-; the amino acid residue of serine is -C(CH 2 OH)-, and so forth.
  • amino acid is therefore intended to include ⁇ -amino acids, ⁇ -amino acids, ⁇ -amino acids, and so forth, and all optical isomers thereof.
  • amino acids include alanine, asparagine, ⁇ /- ⁇ -trityl-asparagine, aspartic acid, aspartic acid- ⁇ -t-butyl ester, arginine, ⁇ -Mtr-arginine, cysteine, S-trityl-cysteine, glutamic acid, glutamic acid- ⁇ -t-butyl ester, glutamine, ⁇ /- ⁇ -trityl-glutamine, glycine, histidine, ⁇ / im -trityl-histidine, isoleucine, leucine, lysine, AT-Boc-lysine, methionine, phenylalanine, praline, serine, O-f-butyl-serine,
  • Carbocyclyl refers to a stable 3- to 15-membered ring radical consisting solely of carbon and hydrogen atoms.
  • the carbocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, and may include fused or bridged ring systems, and the ring system may be partially or fully saturated or aromatic, and the carbon atoms in the ring system may be optionally oxidized.
  • carbocyclyl radicals include, but are not limited to, cycloalkyi radicals (as defined herein), norbomane, norbomene, adamantyl, bicyclo[2.2.2]octane, phenyl, naphthalenyl, indanyl, indenyl, azulenyl, fluorenyl, anthracenyl, and the like.
  • the carbocyclyl ring may be substiuted by R 6 as described above in the Summary of the Invention, or by one or more substituents selected from the group consisting of hydroxy, mereapto, halo, alkyl, alkenyl, alkynyl, phenyl, phenylalkyi, phenylalkenyl, alkoxy, phenoxy, phenylalkoxy, haloalkyi, haloalkoxy, formyl, nitro, cyano, cycloalkyi, hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amidino, ureido, alkoxycarbonyamino, amino, monoalkylamino, dialkylamino, monophenylamino, monophenylalkylamino, sulfonylamino, akylsulfonylamino, aminoalkyl, monoalkyia
  • Cycloalkyi refers to a stable 3- to 10-membered monocyclic or bicyclic radical which is saturated, and which consist solely of carbon and hydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclobutyl, cyclohexyl, decalinyl and the like. Unless otherwise stated specifically in the specification, the term “cycloalkyi” is meant to include cycloalkyi radicals which are optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, hydroxy, amino, cyano, nitro, alkoxy, carboxy and alkoxycarbonyl. "Carboxy” refers to the radical of the formula -C(O)OH.
  • Carboxyalkyl refers to a radical of the formula -R a -C(0)OH where R a is an alkyl radical as defined above, e.g., carboxymethyl, 2-carboxyethyl, 3-carboxypropyl, and the like.
  • Di(alkoxy)alkyI refers to a radical of the formula -R a (-OR a ) 2 where each R a is independently an alkyl radical as defined above and where the -OR a groups may be attached to any carbon in the R a group, e.g., 3,3-dimethoxypropyl, 2,3-dimethoxypropyl, and the like.
  • Dialkylamino refers to a radical of the formula -N(R a )R a where each R a is independently an alkyl radical as defined above, e.g., dimethylamino, diethylamino, (methyl)(ethyl)amino, and the like.
  • Dialkylaminocarbonyl refers to a radical of the formula -C(O)N(R a )R a where each R a is independently an alkyl radical as defined above, e.g., dimethylaminocarbonyl, methylethylaminocarbonyl, diethylaminocarbonyl, dipropylaminocarbonyl, ethylpropylaminocarbonyl, and the like.
  • Dialkylaminosulfonyl refers to a radical of the formula -S(0) 2 N(R a )R a where each R a is independently an alkyl radical as defined above, e.g., dimethylaminosulfonyl, methylethylaminosulfonyl, diethylaminosulfonyl, dipropylaminsulfonyl, ethylpropylaminosulfonyl, and the like.
  • Halo refers to bromo, chloro, iodo or fluoro.
  • Haloalkyi refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1 -fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like.
  • Haloalkoxy refers to a radical of the formula -OR d where R d is an haloalkyi radical as defined above, e.g., trifluoromethoxy, difluoromethoxy, trichloromethoxy, 2,2,2-trifluoroethoxy, 1-fluoromethyl-2-fluoroethoxy, 3-bromo-2-fluoropropoxy, 1 -bromomethyl-2-bromoethoxy, and the like.
  • Heterocyclyl refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the heterocyclyl radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized; and the heterocyclyl radical may be partially or fully saturated or aromatic.
  • the heterocyclyl radical may be attached to the main structure at any heteroatom or carbon atom which results in the creation of a stable compound.
  • heterocyclyl radicals include, but are not limited to, azepinyl, azetidinyl, acridinyl, benzimidazolyl, benzodioxolyl, benzodioxanyl, benzothiazolyl, benzoxazolyl, benzopyranyl, benzofuranyl, benzothienyl, carbazolyl, cinnolinyl, decahydroisoquinolyl, dioxolanyl, furyl, isothiazolyl, quinuclidinyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, indolyl, isoindolyl, indoiinyl, isoindolinyl, indolizinyl, isoxazolyl, isoxazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl,
  • the heterocyclyl radical may be optionally substituted by R 6 as defined above in the Summary of the Invention or may be optionally substituted by one or more substituents selected from the group consisting of hydroxy, mereapto, halo, alkyl, alkenyl, alkynyl, phenyl, phenylalkyi, phenylalkenyl, alkoxy, phenoxy, phenylalkoxy, haloalkyi, haloalkoxy, formyl, nitro, cyano, amidino, cycloalkyi, hydroxyalkyl, alkoxyalkyl, phenoxyalkyl, phenylalkoxyalkyl, amidino, ureido, alkoxycarbonyamino, amino, monoalkylamino, dialkylamino, monophenylamino, monophenylalkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl, monophen
  • Linker residue refers to any component capable of being selectively cleaved to release the residue of the compound of the invention from the solid support. See, e.g., Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., Wiley (1991). Specific linker residues and cleavage reagents for them are depicted in Table 7 below.
  • “Monoalkylamino” refers to a radical of the formula -N(H)R a where R a is an alkyl radical as defined above, e.g., methylamino, ethylamino, propylamino, and the like.
  • “Monoalkylaminocarbonyl” refers to a radical of the formula -C(O)N(H)R a where R a is an alkyl radical as defined above, e.g., methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, and the like.
  • “Monoalkylaminosulfonyl” refers to a radical of the formula -S(O) 2 N(H)R a where R a is an alkyl radical as defined above, e.g., methylaminosulfonyl, ethylaminosulfonyl, propylaminosulfonyl, and the like.
  • ⁇ /-heterocyclyl refers to a heterocyclyl radical as defined above which contains at least one nitrogen atom and which is attached to the main structure through the nitrogen atom.
  • the ⁇ /-heterocyclyl radical may contain up to three additional hetero atoms.
  • Examples include piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, azetidinyl, indolyl, pyrrolyl, imidazolyl, tetrahydroisoquinolyl, perhydroazepinyl, tetrazolyl, triazolyl, oxazinyl, and the like, and may be optionally substituted as described above for heterocyclyl radicals.
  • the ⁇ /-heterocyclyl radical may also be optionally substituted by R 6 as defined above in the Summary of the Invention.
  • Phenylalkyi refers to an alkyl radical as defined above substituted by a phenyl radical, e.g., benzyl, and the like.
  • Phenylalkenyl refers to an alkenyl radical as defined above substituted by a phenyl radical.
  • pharmaceutically acceptable salt refers to salts prepared from pharmaceutically acceptable non-toxic acids or bases including inorganic acids and bases and organic acids and bases.
  • salts may be prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Suitable pharmaceutically acceptable acid addition salts for the compounds of the present invention include acetic, benzenesulfonic (besylate), benzoic, camphorsulfonic, citric, ethenesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic, and the like.
  • suitable pharmaceutically acceptable base addition salts for the compounds of the present invention include metallic salts made from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc or organic salts made from lysine, ⁇ /, ⁇ /'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine ( ⁇ /-methylglucamine) and procaine.
  • Solid support refers to the material upon which synthesis of the compounds of the invention may be performed, and may be also referred to herein as beads or resins.
  • solid support is intended to include beads, pellets, disks, fibers, gels, or particles such as celluslose beads, pore-glass beads, silica gels, polysteyrene beads optionally cross-linked with divinylbenzene and optionally grafted with polyethylene glycol and optionally functionalized with amino, hydroxy, carboxy, or halo groups, grafted co-poly beads, poly-acrylamide beads, latex beads, dimethylacrylamide beads optionally cross-linked with ⁇ /, ⁇ /'-b/s-acryloyl ethylene diamine, glass particles coated with hydrophobic polymer, etc., i.e., material having a rigid or semi-rigid surface; and soluble supports such as low molecular weight non-cross-linked polystyrene.
  • “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for conditions resulting from an abnormality in nitric oxide production.
  • the amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • Treating covers the treatment of a condition in a human, which condition results from an abnormality in nitric oxide production, and includes:
  • Nitric oxide generated by the inducible form of nitric oxide synthase has been implicated in the pathogenesis of numerous inflammatory and autoimmune diseases and also in diseases which are generally not regarded as inflammatory, but nevertheless may involve cytokines which locally up-regulate i-NOS.
  • the compounds of the invention alone or in combination with other pharmaceutical agents, are therefore useful in treating mammals, preferably humans, having a condition resulting from an abnormality in nitric oxide production.
  • Such conditions include, but are not limited to, the following: Multiple sclerosis (Parkinson, J.F. et al., J. Mol. Med. (1997), Vol. 75, pp.
  • pathogen-mediated pneumonias (Adler, H. et al., J. Exp. Med. (1997), Vol. 185, pp. 1533-1540); trauma of various etiologies (Thomae, K.R. et al., Surgery (1996), Vol. 119, pp. 61-66); rheumatoid arthritis and osteoarthritis (Grabowski, P.S. etal., Br. J. Rheumatol. (1997), Vol. 36, pp. 651-655); glomerulonephritis (Weinberg, J.B. et al., J. Exp. Med. (1994), Vol. 179, pp.
  • diabetic neuropathy or nephropathy Sugimoto, K. and Yagihashi, S., Microvasc. Res. (1997), Vol. 53, pp. 105-112; Amore, A. et al., Kidney Int. (1997), Vol. 51 , pp. 27-35); acute and chronic organ transplant rejection (Worrall, N.K. et al., Transplantation (1997), Vol. 63, pp. 1095-1101); transplant vasculopathies (Russell, M.E. et al., (1995), Vol. 92, pp. 457-464); graft-versus-host disease (Kichian, K. et al., J.
  • the compounds of the current invention may also be useful for the management of male and female reproductive functions when used alone or combined with other drugs commonly used for these indications.
  • Examples include: inhibition of fertilization, endometrial receptivity and implantation (alone or in combination with a progesterone antagonist); post-coital contraception (alone or in combination with a progesterone antagonist); induction of abortion (in combination with an antiprogestin and in further combination with a prostaglandin); control and management of labor and delivery; treatment of cervical incompetence (alone or in combination with progesterone or a progestin); treatment of endometriosis (alone or in combination with other drugs, including LHRH- agonists/antagonists, antiprogestins orprogestins by either sequential application or by concomitant administration).
  • the compounds of the present invention include 1 -substituted imidazoles.
  • This class of compounds has previously been described as mechanism-based, heme-binding inhibitors of the cytochrome P450 family of enzymes (Maurice, M. et al., FASEB J. (1992), Vol. 6, pp. 752-8) in addition to nitric oxide synthesis (Chabin, R.NM. et al., Biochemistry (1996), Vol. 35, pp. 9567-9575).
  • the compounds of the present invention may thus be useful as inhibitors of selected cytochrome P450 family members of therapeutic interest including, but not limited to, P450 enzymes involved in steroid and retinoid biosynthesis (Masamura et al., Breast Cancer Res. Treat. (1995), Vol. 33, pp. 19-26; Swart, P. et al., J. Clin. Endocrinol. Metab., Vol. 77, pp. 98-102; Docks, P. et al., Br. J. Dermatol. (1995), Vol. 133, pp. 426-32) and cholesterol biosynthesis (Burton, P.M. et al., Biochem. Pharmacol. (1995;, Vol. 50, pp.
  • Imidazole-based compounds may also have antifungal activity (Aoyama, Y. et al., Biochem. Pharmacol. (1992), Vol. 44, pp. 1701-1705).
  • the P450 inhibitory activity of the compounds of the present invention can be assessed using appropriate assay systems specific for the P450 isoform of interest. Such assays are included in the references cited above.
  • cytochrome P450 3A4 which can be assayed in a manner similar to the method described in Yamazaki et al., Carcinogenesis (1995), Vol. 16, pp. 2167-2170.
  • Nitric oxide synthases are complex enzymes that catalyze the conversion of L-arginine to nitric oxide (NO) and citrulline. Catalysis proceeds through two successive oxidations of the guanidinium group of L-arginine.
  • a cell-based nitric oxide synthase assay employing the measurement of nitric oxide oxidation product, nitrite, in the conditioned medium of cultured cells was employed for the evaluation of the compounds of the invention.
  • the murine monocytic cell lines RAW 264.7 and J774 are well documented as capable of producing >10 ⁇ M nitrite in response to immunostimulation: Induction of iNOS in RAW 264.7 Mouse Monocvtes
  • RAW 264.7 murine macrophage cells were obtained from American Type Culture Collection (Rockville, Maryland) and were maintained in RPM1 1640 containing 10% fetal bovine serum (FBS), 5000 units/mL of penicillin and streptomycin, and 2mM glutamine (maintenance medium). NOS activity was measured by a fluorescent assay of the nitric oxide oxidation product, nitrite, (Diamani et al., Talanta (1986), Vol. 33, pp. 649-652). Induction of iNOS (inducible nitric oxide synthase) is stimulated by treatment of the cells with lipopolysaccharide and ⁇ -interferon. The method of the assay is described below.
  • Cells are harvested, diluted to 500,000 cells/mL with maintenance medium, and seeded into 96-well plates at 100 ⁇ l/well. The plates are incubated ovemight at 37 ⁇ C, under a 5% CO 2 atmosphere. The medium is then replaced with 90 ⁇ l of BME medium containing 10% FBS, 100 units/mL of penicillin, 100 ⁇ l streptomycin, 2 mM glutamine, 100 units/mL of interferon- ⁇ and 2 ⁇ g/mL of lipopoly-saccharide.
  • ⁇ /-guanidino-methyl-L-arginine is added to four wells (negative control) at a final concentration of 200 ⁇ M using 10 ⁇ l of 2 mM stock solution in 100 mM Hepes, pH 7.3 + 0.1% DMSO and four wells receive only the 100 mM Hepes/0.1% DMSO buffer (positive control).
  • Compounds for evaluation are dissolved at 10-fold the desired final concentration in Hepes/DMSO and 10 ⁇ L of these solutions is transferred to the 96-well plate. The plates are incubated for 17 hrs at 37°C, under a 5% CO 2 atmosphere.
  • Nitrite accumulated in the culture medium is determined as follows: add 15 ⁇ L of 2,3-diaminonaphthalene (10 ⁇ g/mL in 0.75 M HCI) to each well and incubate for 10 minutes at room temperature. Add 15 ⁇ l of 1 N NaOH and measure the fluorescence emission at 405 nm, using an excitation wavelength of 365 nm. Enzyme activity in experimental wells is normalized to percent control using the positive and negative control values. The signal to noise ratio is >10 for the assay.
  • the compounds of the invention when tested in this assay, demonstrated the ability to inhibit nitric oxide production.
  • Various in vivo assays may be employed to determine the efficacy of the compounds of the invention in treating a condition resulting from an abnormality in nitric oxide production, such as arthritis.
  • the following is a description of such an assay utilizing rats: Effects of Compounds of the Invention on Adiuvant-lnduced Arthritis in Rats
  • mice were injected intradermally (proximal quarter of the tail) with 0.1 mL of Mycobacterium butyricum in Incomplete Freund's Adjuvant (10 mg/mL). Either vehicle (acidified saline, 1 mUkg) or a compound of the invention (3, 10, or 30 mg/kg) were administered subcutaneously (b.i.d.), starting on the day following adjuvant immunization, and continued until the end of the experiment (N 10 rats per treatment group). Clinical scores (see below) were measured in all limbs 3 times per week throughout the study. Rats were euthanized 34-35 days after immunization.
  • a radiologic evaluation (see below) of the hind paws was performed, a blood sample was collected for clinical blood chemistry and drug levels (high dose group only; 6 or 12 hours post final dose), a section of liver was obtained for measurement of potential toxicity, and the hind limbs were preserved for histopathological determination.
  • Any suitable route of administration may be employed for providing a patient with an effective dosage of compounds of the invention.
  • oral, rectal, parenteral (subcutaneous, intramuscular, intravenous), transdermal, and like forms of administration may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, patches, and the like.
  • compositions of the present invention comprise the compounds of the invention as the active ingredient, and may also contain a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • Carriers such as starches, sugars, and microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like are suitable in the case of oral solid preparations (such as powders, capsules, and tablets), and oral solid preparations are preferred over the oral liquid preparations. Methods for their preparation are well known in the art. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
  • compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets, each containing a predetermined amount of the active ingredient, as a powder or granules, or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion, or a water-in- oil liquid emulsion.
  • Such compositions may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • a preferred group of compounds of formula (I), formula (II) and formula (III) are those compounds of formula (I) having the formula (la), formula (lb) or formula (lc):
  • a preferred subgroup of this group of compounds are those compounds wherein A is -OR 1 , -C(O)N(R 1 )R 2 , -N(R 16 )C(O)N(R 1 )R 16 , -NR 1 C(0)R 2 or -N(R 1 )R 21 ; V is N(R 4 ); and W is CH.
  • a preferred class of compounds of this subgroup are those compounds wherein A is -C(O)N(R 1 )R 2 ; q, r and n are zero; R 1 is hydrogen; R 2 is lower alkyl or -[C 1 -C 8 ]-R 9 ; R 4 is hydrogen or lower alkyl; and R 5 is hydrogen, halo, alkyl, or alkoxy.
  • a preferred subclass of compounds of this class of compounds are those compounds wherein R 9 is phenyl, tolyl, anisyl, 1 ,4-benzodioxan-6-yl, 1,3-benzodioxol-5-yl, chlorophenyl, carboxyphenyl, dimethoxyphenyl, 2-thienyl or morpholinyl.
  • Another preferred subgroup of compounds of this group of compounds are those compounds where A is -C(0)N(R 1 )R 2 ; m is zero; Q is a direct bond to R 3 ; and R 3 is hydrogen.
  • a preferred compound of this subgroup is ⁇ /-[(1 ,3-benzodioxol-5-yl)ethyl]-2-[[2-(1H- imidazol-1-yl)-6-methylpyrimidin-4-yl](methyl)amino]acetamide.
  • Another preferred group of compounds of formula (I), formula (II) and formula (III) are those compounds of formula (II) having the formula (lla), formula (lib) or formula (He):
  • a preferred subgroup of compounds of this group of compounds are those compounds wherein the ⁇ /-heterocyclyl is selected from the group consisting of piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, azetidinyl, indolyl, pyrrolyl, imidazolyl, tetrahydroisoquinolyl, and perhydroazepinyl.
  • a preferred class of compounds of this subgroup of compounds are those compounds wherein the ⁇ /-heterocyclyl is piperazinyl substituted by R 6 , i.e., the compound of formula (lid), formula (lie) or formula (llf):
  • a preferred subclass of compounds of this class of compounds are those compounds where A is -OR 1 , -C(O)N(R )R 2 , -N(R 16 )C(O)N(R 1 )R 16 , -NR 1 C(O)R 2 or -N(R 1 )R 21 ;
  • W is CH; and R 6 is chosen from the group consisting of hydrogen, alkyl, cycloalkyi, -[C C 8 alkyl]-R 8 , -[C 2 -C 8 alkyl]-R 10 , -[C,-C 8 alkyl]-R 11 , acyl, -C(O)R 8 , -C(O)-[C C 8 alkyl]-R 8 , alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aralkoxycarbonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heterocycly
  • preferred compounds are those compounds wherein A is -C(0)N(R 1 )R 2 ; R 1 is hydrogen; R 2 is lower alkyl, -[C C 8 alkyl]-R 9 , or -[C r C 8 ]-R 10 ;
  • R 6 is hydrogen, acetyl, f-butoxycarbonyl, 4-methoxyphenylaminocarbonyl, 4-methoxyphenyl- methyl, methoxycarbonyl, methyl or benzyl;
  • R 5 is hydrogen, halo, alkyl, or alkoxy; and
  • n is 0 or 1.
  • R 2 is -CH 2 -R 9 or -[C C 8 ]-R 10 ;
  • R 9 is aryl or substituted aryl; and
  • R 10 is methylthio.
  • most preferred compounds are those compounds wherein R 2 is -CH 2 -R 9 ; R 6 is hydrogen, acetyl or t-butoxycarbonyl; and R 9 is phenyl, tolyl, anisyl, 1 ,4-benzodioxan-6-yI, 1 ,3-benzodioxol-5-yl, methylthiophenyl, chlorophenyl, carboxyphenyl, dimethoxyphenyl, or 2-thienyl.
  • preferred compounds are those compounds wherein R 5 is chloro, R 6 is acetyl and R 9 is p-tolyl, or those compounds wherein R 5 is chloro, R 6 is hydrogen and R 9 is p-tolyl, or those compounds wherein R 5 is chloro, R 6 is hydrogen and R 9 is 1 ,4-benzodioxan-6-yl or 1 ,3-benzodioxol-5-yl, or those compounds wherein R 5 is chloro, R 6 is t-butoxycarbonyl and R 9 is 1 ,4-benzodioxan-6-yl or 1 ,3-benzodioxol-5-yl.
  • Preferred compounds of this subgroup of compounds may be selected fro m the following list:
  • Another preferred class of compounds of this subgroup of compounds are those compounds wherein the ⁇ /-heterocyclyl is piperidinyl, i.e., the compound of formula (llg), formula (llh) or formula (Hi):
  • a preferred subclass of compounds of this class of compounds are those compounds wherein A is -OR 1 , -C(0)N(R )R 2 , -N(R 6 )C(0)N(R 1 )R 16 , -NR 1 C(0)R 2 or -N(R 1 )R 21 ; and W is CH.
  • Preferred compounds of this subclass of compounds are those compounds wherein A is -C(0)N(R 1 )R 2 ; R 1 is hydrogen; R 2 is lower alkyl or -[C C 8 alkyl]-R 9 ; R 5 is hydrogen, halo, alkyl, or alkoxy; and n is zero or one. More preferred compounds of these preferred compounds are those compounds where R 2 is lower alkyl or -CH 2 -R 9 and R 9 is 4-methoxyphenyl, 1 ,4-benzodioxan-6-yl, 1 ,3-benzodioxol-5-yl or 3,4-dimethoxyphenyl.
  • Preferred compounds of this subgroup of compounds may be selected from the following list: ⁇ /-[(1 ,3-benzodioxol-5-yl)methyl]-1-[2-(1 /-/-imidazol-1-yl)pyrimidin-4-yl]piperidine-2- ethanamine;
  • Another preferred class of compounds of this subgroup of compounds are those compounds wherein the ⁇ /-heterocyclyl is pyrrolidinyl, i.e., the compound of formula (llj), formula (Ilk) or formula (llm):
  • a preferred subclass of compounds of this class of compounds are those compounds wherein A is -OR 1 , -C(0)N(R 1 )R 2 , -N(R 16 )C(0)N(R 1 )R 16 , -NR 1 C(0)R 2 or -N(R 1 )R 21 ; and W is CH.
  • Preferred compounds of this subclass of compounds are those compounds wherein A is -C(0)N(R 1 )R 2 ; R 1 is hydrogen; R 2 is lower alkyl or -[C r C 8 alkyl]-R 9 ; R 5 is hydrogen, halo, alkyl, or alkoxy; and n is zero or one. More preferred compounds of the preferred compounds are those compounds having the R-configuration at C-2 of the pyrrolidinyl ring. Preferred compounds of this subgroup of compounds may be selected from the following list:
  • Additional preferred compounds of the group of compounds as defined above may be selected from the following list: 4-[2-(1/-/-imidazol-1-yl)pyrimidin-4-yl]- ⁇ /-[(1,3-benzodioxol-5-yl)ethyl]morpholine-2- carboxamide;
  • a preferred subgroup of compounds of this group of compounds are those compounds
  • Another preferred group of compounds of formula (I), formula (II) or formula (III) are those compounds wherein each X, Y or Z is C(R 19 ), and each U is C(R 5 ).
  • Another preferred group of compounds of formula (I), formula (II) or formula (III) are those compounds wherein each X, Y or Z is N, and each U is C(R 5 ).
  • Another preferred group of compounds of formula (I), formula (II) or formula (III) are those compounds wherein each X is N, each Z or Y is C(R 19 ), and each U is N.
  • Another preferred group of compounds of formula (I), formula (II) or formula (III) are those compounds wherein in each formula, one of X, Y, and Z is N and the others are C(R 19 ), and U is C(R 5 ).
  • a preferred group of compounds of formula (IV) are those compounds of formula (IVa), formula (IVb) or formula (IVc):
  • a preferred subgroup of compounds of this group of compounds are those compo unds wherein said amino acid is an ⁇ -aminoacid of the L configuration at the carbon ⁇ to the acid.
  • Another preferred subgroup of compounds of this group of compounds are those compounds wherein said amino acid is an ⁇ -aminoacid of the D configuration at the carbon a to the acid.
  • R 1 is hydrogen
  • R 2 is lower alkyl or -[C C 8 alkyl]-R 9
  • R 5 is hydrogen, halo, alkyl, or alkoxy.
  • R 9 is phenyl, tolyl, anisyl, 1 ,4-benzodioxan-6-yl, 1 ,3-benzodioxol-5-yl, chlorophenyl, carboxyphenyl, 2-thienyl, dimethoxyphenyl or morpholinyl.
  • a preferred group of compounds of formula (Va), formula (Vb) or formula (Vc) are those compounds wherein each X and each Y is N; each W is CH; and B is a fused optionally substituted heterocyclyl.
  • a preferred subgroup of compounds of this group of compounds are those compounds having the formula (Vba):
  • A is -OR 1 , -C(0)N(R )R 2 , -N(R 16 )C(0)N(R 1 )R 16 , -NR 1 C(0)R 2 or -N(R 1 )R 21 ;
  • a preferred compound of this subgroup of compounds is ⁇ /-[(1 ,3-benzodioxol-5- yl)methyl]-1-[2-(1H-imidazol-1-yl)purin-6-yl]piperidine-2-acetamide.
  • a preferred compound is ⁇ /-[(1 ,3-benzodioxol-5-yI)methyl]-1-[6-chloro-2-(pyridin-3-yl)pyrimidin-4- yl]piperidine-2-acetamide.
  • the compounds of the invention may be synthesized by two general approaches, one of which (solid phase) could be thought of as a variant of the other (solution phase).
  • the solution phase generic synthesis is shown in the following Reaction Scheme 1 which, for illustration purposes only, illustrates the synthesis of a compound of formula (I) where A is -C(0)N(R 1 )R 2 . It is understood that other compounds of the invention may be prepared in a similar manner.
  • PG is a suitable protecting group
  • m, n, q, r, Q, U, W, X, Y and Z are as described above in the Summary of the Invention
  • V is N(R 4 ), S or O (where R 4 is as described in the Summary of the Invention)
  • R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 17 , and R 20 are as described above in the Summary of the Invention:
  • the compounds of formula (I) are prepared by first adding one equivalent of a compound of formula (XI) in one portion to a solution of one equivalent of a compound of formula (XII) having at least two substituents displaceable by a nucleophile and 1.1 equivalents of a trialkyl amine base (such as triethylamine) in a polar, nonprotic solvent such as THF or methylene chloride to provide the compound of formula (XIII). Upon completion of the reaction, the mixture is purified by conventional methods.
  • the compounds of formula (XIVcc) are synthesized by methods well known in the amino acid and peptide synthetic art from the appropriate compound of formula (XlVaa), wherein PG is a standard protecting group for the V subsituent.
  • Compounds of formula (XlVaa) are commercially available, usually in protected form, or are readily synthesized by procedures well-known in the art.
  • Preferred protecting groups are Boc ( t-butoxycarbonyl) and Fmoc (fluorenylmethoxy-carbonyl), although others, such as CBZ (benzyloxycarbonyl), and Troc (trichloroethoxycarbonyl), could be used for particular circumstances.
  • the compounds of formula (I) in which A is a urea may be prepared by reacting a compound of formula (I) where A is -N(R 1 )R 21 (where R 1 is hydrogen and R 21 is hydrogen, alkyl, aryl or aralkyl) with an isocyanate.
  • the compounds of formula (I) in which A is a carbamate may be prepared by reacting a compound of formula (I) (where A is -N(R 1 )R 21 where R 1 is hydrogen and R 21 is hydrogen, alkyl, aryl or aralkyl) with an alkyl chloroformate or by Curtius rearrangement of the carboxylic acid azide of the compound of formula (XlVaa) in the presence of the appropriate alcohol.
  • a specific embodiment of the generic synthesis of a compound of the invention is shown below in Reaction Scheme 2 as applied to a 6-chloro-2-(1-imidazolyl)-4-pyrimidinamine that incorporates the residue of D- ⁇ -thienylalanine piperonylamide:
  • Imidazole (9.5 g, 140 mmol) was added in one portion to a solution of trichloropyrimidine (24.7 g, 135 mmol) and triethylamine (30 mL, 216 mmol) in THF (500 mL). After 16 hrs, the reaction mixture was poured into saturated, aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over MgS0 4 . The reaction mixture was filtered and all volatiles were removed under reduced pressure.
  • Boc-pyrrolidine (3.0 g, 17.5 mmol) was dissolved in ether (35 ml) and tetramethylethylenediamine (TMEDA) (2.03 g, 17.5 mmol), cooled to -78 °C and s-butyllithium (1.3 M, 13.5 mL, 18 mmol) was added. After stirring for 1 hour, allyl bromide was added in ether (5 mL). After warming to room temperature, the reaction was quenched with water and the organic layer was separated. The organic layer was washed with 1 M solution of NaH 2 P0 4 and water, then dried over MgS0 4 .
  • TEDA tetramethylethylenediamine
  • the dichlorotriazine (20 mg, 0.047 mmol) was dissolved in THF and reacted with TMS-imidazole (0.009 mL, 0.06 mmol) and CsF (11 mg, 0.07 mmol) at 0 °C . After warming to room temperature and stirring for 4 hours, the reaction was diluted with ethyl acetate and washed with saturated NH 4 CI, water, and brine.
  • the pyrimidine was dissolved in THF/water (1/1) and LiOH (6 mg, 0.21 mmol) was added. After heating at 60 °C for 3 hours, the solvent was removed in vacuo and acidified with methanolic HCI. The solvent was removed in vacuo, dissolved in DMF and treated with HATU (42 mg, 0.11 mmol), DIEA (37 mg, 0.21 mmol), and piperonylamine (26 mL, 0.21 mmol). After stirring for 18 hours, the solvent was removed in vacuo, the residue was dissolved in CH 2 CI 2 , and washed with saturated NaHC0 3 and brine.
  • Another specific embodiment of the generic synthesis as applied to a compound of the invention is ⁇ /-[(1 ,3-benzodioxol-5-yl)ethyl]-1 -[2-(1 /-/-imidazol-1 -yl)pyrimidin-4-yl]pyrrole-2- carboxamide [MS: (403.2 M+H) + ], which was prepared in a similar manner described above for ⁇ /-[(1 ,3-benzodioxol-5-yl)methyl]-1 -[2-(1 H-imidazol-1 -yl)pyrimidin-4-yl]indole-6-carboxamide.
  • Reaction Scheme 3 depicts a method of preparing the compounds of the invention where U is CR 5 (where R 5 is hydrogen) and X, Y and Z are CR 19 (where R 19 is hydrogen):
  • the above synthesis may be carried out as follows: To benzene (20 mL) was added 1-(3-aminophenyl)imidazole (755 mg, 4.7 mmol), 7-chloro-3-oxoheptanoic acid ethyl ester (982 mg, 4.7 mmol), Na 2 HP0 4 (667 mg, 4.7 mmol), l 2 (60 mg, 0.23 mmol), and 4A molecular sieves (500 mg). After refluxing for 6 hours, more 1 2 (60 mg) was added.
  • This ester (120 mg, 0.38 mmol) was dissolved in MeOH (20 mL) and reacted with 10% Pd/C (60 mg) and 1 atm of H 2 . After reacting for 60 hours, the reaction was filtered, the solvent removed in vacuo, and the residue chromatographed (ethyl acetate/hexanes, 1/1) to give 24 mg of 1-[3- (1/-/-imidazol-1-yl)phenyl]piperidine-2-acetic acid ethyl ester (compound of formula (XV)). This ester (24 mg, 0.076 mmol) was dissolved in 5% methanolic NaOH.
  • reaction was acidified with methanolic HCI, the solvent removed in vacuo, and the residue dissolved in DMF. Piperonylamine (1 eq), H ⁇ nig's base (2 eq) and HATU (1 eq) were added. After reaction completion the reaction mixture was partitioned with water and ethyl acetate. The organic layer was separated, washed with water, and dried.
  • Reaction Scheme 4 depicts a method of preparing compounds of the invention where A is -OR 1 :
  • the above synthesis may be carried out as follows: To DMF (100 ml) was added 4-chloro-2-imidazol-1-ylpyrimidine (0.50 g, 2.77 mmol), 2-piperidineethanol (0.359 g, 2.77 mmol), and H ⁇ nig's base (0.536 g, 4.15 mmol).
  • the above synthesis may be carried out as follows: To a solution of 1-[(1 H-imidazol-1- yl)pyrimidin-4-yl]piperidine-2-ethanol (the compound of formula (XVI)) (236 mg, 0.86 mmol) and methanesulfonyl chloride (99 mg, 0.87 mmol) dissolved in CH 2 CI 2 (20 mL) was added TEA (87.5 mg, 0.87 mmol). After stirring for 16 hours at 0 °C, methanesulfonyl chloride (99 mg, 0.87 mmol) and TEA (87.5 mg, 0.87 mmol) were added and the solution was warmed to ambient temperature.
  • Reaction Scheme 6 depicts another method of preparing compounds of the invention where V is C(R 4 )H:
  • the above synthesis may be carried out as follows: To a solution of LDA (1.28 g, 12 mmol) in THF (30 mL) at -78 °C was added 2,4-dichloro-6-methylpyrimidine (1.96 g, 12 mmol) in THF (15 mL). After stirring for 15 minutes, 3,3-dimethylallyl bromide (1.79 g, 12 mmol) in THF (5 mL) was added dropwise. After the reaction warmed to ambient temperature, water and ethyl acetate was added.
  • Imidazole was added under standard conditions (1-trimethylsilylimidazole and CsF in DMF at 60 °C) to give ⁇ /-[(1,3-benzodioxol-5-yl)ethyl]-6- chloro-2-(1H-imidazol-1-yl)pyrimidine-4-propionamide (the compound of formula (Ihh)); MS: 386 (M+H) + .
  • the solid phase generic synthesis may be conceptualized as the generic synthesis of Reaction Scheme 1 in which R 1 has been replaced by a cleavable attachment to a derivatized polymer resin. At the end of the synthetic scheme, the resin is cleaved and R 1 becomes hydrogen.
  • the solid phase synthetic scheme is illustrated in Reaction Scheme 7 as applied to the specific example, as before, of a piperonylamide, but in this case the amino acid is piperazine-2-acetic acid:
  • the group which is to become R 1 is attached to the resin through a cleavable linkage, such as the 2-nitrobenzyl residue, which can be photolytically cleaved.
  • a cleavable linkage such as the 2-nitrobenzyl residue, which can be photolytically cleaved.
  • the piperonylamine (see above) has been protected with Boc and reacted with 4-(bromomethyl)-3-nitrobenzoic acid to produce the Boc-protected compound of formula (XXI), which is then attached to a free amine of the lysine-derivatized, amino- functionalized synthetic support.
  • a polyethyleneglycol-grafted crossliked polystyrene, 1% DVB crosslinked polystyrene or crosslinked polydimethylacrylamide is suspended in a polar aprotic solvent such as methylene chloride, DMF or THF.
  • a coupling reagent such as diisopropylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC), b/s(2-oxo-3- oxazolidinyl)phosphinic chloride (BOP), or 0-(7-azabenzotriazol-1-yl)-1 ,1,3,3- tetramethyluronium-hexafluorophosphate (HATU) and optionally an acylation catalyst such as dimethylaminopyridine (DMAP) or hydroxybenzotriazole (HOBT).
  • DMAP dimethylaminopyridine
  • HOBT hydroxybenzotriazole
  • the mixture is agitated at ambient temperature for 1 to 24 hours or until the reaction is complete as judged by a ninhydrin test.
  • the resin is washed with an appropriate solvent or solvents multiple times to remove excess reagents and by-products to give the resin-compound of formula (XXII).
  • the resin-compound of formula (XXII) is deprotected to liberate the compo und of formula (XXIII), which is then suspended in a polar aprotic solvent such as methylene chloride or DMF.
  • a polar aprotic solvent such as methylene chloride or DMF.
  • An excess of an appropriately protected compound of formula (XXIV) is added followed by a coupling agent such as HATU, BOP or DIC with the optional addition of an acylation catalyst such as DMAP or HOBT.
  • an excess of an activated form of the compound of formula (XXIV), such as the symmetrical anhydride or acyl fluoride may be added to the resin.
  • the mixture is shaken for 1 to 24 hours at ambient temperature and then washed multiple times with an appropriate solvent or solvents to remove excess reagents and by- products to give the resin-compound of formula (XXV).
  • Resin-compound of formula (XXV) is deprotected to liberate the compound of formula (XXVI), which is then suspended in a polar aprotic solvent such as DMF or THF.
  • a polar aprotic solvent such as DMF or THF.
  • An excess of the appropriate compound of formula (Vlllb) is added followed by an excess of a base such as triethylamine or diisopropylethylamine.
  • the mixture is agitated and heated to 50-100°C for 1 to 24 hours, then cooled and washed multiple times with an appropriate solvent to remove excess reagents and by products to give resin-compound of formula (IXaa).
  • the resin-compound of formula (IXaa) is optionally treated to liberate protected functionality incorporated as part of a synthon to produce the compound of formula (Hi).
  • Resin-compound of formula (XXV) is deprotected with piperidine to liberate an amine and then dissolved or suspended in an inert solvent, such as methylene dichloride.
  • an inert solvent such as methylene dichloride.
  • An excess of an appropriately protected acid that will furnish R 6 is added followed by a coupling agent such as HATU, BOP or DIC with the optional addition of an acylation catalyst such as DMAP or HOBT.
  • an excess of an activated form of the acid such as the symmetrical anhydride or acyl fluoride may be added to the resin.
  • the mixture is shaken for 1 to 24 hours at ambient temperature and then washed multiple times with an appropriate solvent or solvents to remove excess reagents.
  • the product is suspended in a polar aprotic solvent, such as DMF or THF.
  • An excess of the appropriate compound of formula (Vlllb) is added followed by an excess of a base such as triethylamine or diisopropylethyl-amine.
  • the mixture is agitated and heated to 50-100°C for 1 to 24 hours, then cooled and washed multiple times with an appropriate solvent to remove excess reagents and by products to give resin compounds analogous to the resin-compound of formula (IXaa), but having the pyrimidine attached to the piperazineacetic acid at the 4-position.
  • This resin compound analogus to the resin-compound of formula (IXaa) is then suspended in a protic solvent such as methanol or acetonitrile-water and stirred and photolyzed to cleave the product from the resin. Filtration, and evaporation of the filtrate gives the crude product, which is then purified and characterized by standard techniques.
  • a protic solvent such as methanol or acetonitrile-water
  • Filtration, and evaporation of the filtrate gives the crude product, which is then purified and characterized by standard techniques.
  • 1.57 g of an amino-functionalized TentaGel resin (0.80 mmole) was suspended in 20 mL of methylene chloride and treated with 1.05 g of linker acid (2.4 mmole), 0.50 mL of DIC (3.2 mmole), and 20 mg of DMAP (0.16 mmole).
  • the final product was cleaved from the resin by photolysis in methanol (MeOH) for 17 hours to give 54.6 mg of product, a compound of formula (Hi) (31%).
  • the crude product was purified by flash chromatography (eluted with 4:4:1 ethyl acetate:hexanes:MeOH).
  • the Boc-protected amine product was treated with 3 mL of 30% TFA-methylene chloride for 1 hour and was dried in vacuo to give quantitative amount of product.
  • the piperazineacetic acid compound of formula (XXIV) employed in the synthesis above and many others in this application was synthesized as follows: Twelve milliliters (50 mmol) of ⁇ /, ⁇ /'-dibenzylethylene-diamine, 14 mL (100 mmol) of Et 3 N and 250 mL toluene were combined at 0°C, and 7 mL (50 mmol) of methyl 4-bromocrotonate (7 mL, 50 mmol) was added. The reaction was slowly warmed to room temperature, stirred for 24 hours, filtered, concentrated in vacuo to a residue and treated with 10% aqueous HCI (300 mL).
  • the reaction was stirred at 0° for 1 hour, allowed to warm up to room temperature, stirred for 2 hours, and extracted with ethyl acetate (2x200 mL).
  • the combined extracts were treated with 50 mL of 10% HCI (aqueous).
  • the aqueous layer was washed with ethyl acetate, basified with K 2 C0 3 and extracted three times with ethyl acetate.
  • a portion (5.2 g; 20 mmol) of the methyl 4-Boc-piperazine-2-acetate product from the previous step was combined with 60 mL of THF and 60 mL of 1 N NaOH (aqueous) and stirred at room temperature for 6 hours to saponify the methyl ester.
  • the reaction was cooled to 0°C, adjusted to pH 9-10 with 10% HCI(aqueous), and 5.2 g (20 mmol) of FMOC-CI was added.
  • the starting material was prepared by dissolving 5.25 g (25.85 mmol) of 2-piperazine carboxylic acid-2HCI in 160 mL of 1 :1 dioxane/H 2 0, and adjusting the pH to 11 with 50% NaOH (aq.).
  • a solution of 7.21 g (29.28 mmol) of BOC-ON in 40 mL of dioxane was slowly added (in portions) while maintaining the pH at 11 with 50% NaOH (aq.) during the addition.
  • 4-Boc-morpholine-3-carboxylic acid which can be substituted for the compound of formula (XXIV) in Reaction Scheme 7 above to prepare other compounds of the invention, can be prepared in the following manner: To a solution of 4-phenylmethylmorpholin- 5-one-3-carboxylic acid methyl ester (5.I g. 20.5 mmol) in 100 mL of THF was added borane/DMS (10M, 2.6 mL) slowly while cooling at 0 °C. The solution was allowed to warm to ambient temperature and stirred for 18 hours. Water (100 mL) was then added and the mixture extracted with ethyl acetate. The organic layers were dried over MgSO 4 and concentrated.
  • the resulting oil was purified on a silica gel column eluted with 3:7 ethyhhexanes to yield the morpholine (3.0 g, 64%).
  • the morpholine (3.0 g. 12.75 mmol) was dissolved in 50 mL MeOH and 10% Pd/C (10 mg) was added. The mixture was stirred at ambient temperature under a H 2 atmosphere for 16 hours. The mixture was then filtered through celite and concentrated. The resulting oil was dissolved in CH 2 CI 2 (25 mL) and di-t-butyldicarbonate (2.8 g, 12.75 mmol) was added.
  • 1-Boc-perhydroazepine-2-acetic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: N-Boc- perhydroazepine (1.06 g, 6.16 mmol) in ether is treated with TMEDA (715 mg, 6.16 mmol) followed by sec-butyllithium (1.3 M. 4.74 ml, 6.16 mmol) at -78 °C. The reaction was slowly warmed to -40°C, stirred for 1 hour, cooled to -78 °C and treated with a solution of 3,3- dimethylallyl bromide (918 mg. 6.16 mmol) in ether.
  • 1-Boc-pyrrolidine-2-propionic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: Boc-pyrrolidine (5.0 g, 29.2 mmol) was dissolved in ether (35 ml) and TMEDA (3.0 g, 20 mmol), cooled to -78°C and s-butyllithium (1.3 M, 17 ml, 22 mmol) was added. After stirring for 1 hour, allyl bromide (5.1 mL, 57 mmol) was added. After warming to room temperature, the reaction was quenched with water and the organic layer was separated.
  • 4-Boc-thiomorpholine-3-carboxyiic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF was added cysteine ethyl ester hydrochloride (1.15 g, 6.18 mmol), triethylamine (4.17 mL, 30 mmol) and dibromoethane (2.51 mL, 6.2 mmol). After stirring for 1 hour and refluxing for 16 hours, the solids were removed by filtration. The solvent was removed in vacuo and the residue was chromatographed on silica to give thiomorpholinecarboxylic acid ethyl ester (0.94 g, 87%).
  • 4-Boc-thiomorpholine-3-acetic acid can also be substituted for the compound of formula (XXIV) in Reaction Scheme 7 and can be prepared in the following manner: To THF (50 mL) was added methyl bromocrotonate (1.0 mL, 8.6 mmol), H ⁇ nig's base (1.5 mL, 8.6 mmol), and ⁇ /-Boc-2-aminoethanethiol (1.5 g, 8.6 mmol). After stirring for 3 hours, the reaction was poured into saturated NH 4 CI and extracted with ethyl acetate. The organic layer was washed with brine, dried (MgS0 4 ), and the solvent was removed in vacuo.
  • the ester was dissolved in THF (50 mL) and borane/DMS (3 mL, 30 mmol) was added. After stirring for 16 hours, ethanol was added to quench the reaction. HCI gas was bubbled into the reaction and the mixture was refluxed for 2 hours. The solvent was removed in vacuo and the residue was suspended in 0.5 M NaOH and CH 2 CI 2 . The organic layer was separated, dried (Na 2 S0 4 ), and the solvent was removed in vacuo. Chromatography on silica (MeOH/ethyl acetate) afforded starting material (0.71 g, 29%) and the thiomorpholine (1.26 g, 56%).
  • Reaction Scheme 7 depicts a synthesis in which a preformed, protected compound of formula (XXI) is coupled to the resin and deprotected to allow reaction with the protected compound of formula (XXIV). It will be apparent to the artisan that the sequence of this reaction series could be altered to provide the same deprotected piperonylamino-methyl benzoyl resin. An example of such a sequence follows. This example also illustrates how one would reverse the substitution pattern in the piperazineacetic acid ring.
  • ⁇ /'-Fmoc- ⁇ Boc-piperazine ⁇ -acetic acid (978 mg, 2.1 mmol), HATU (798 mg, 2.1 mmol) and DIEA (542 mg, 4.2 mmol) were mixed in 15 mL of DMF; and then added to the resin. After shaking for 24 hours, the resin was filtered, washed and dried as usual; the resin weighed 1.693 g. The resin was taken in 15 mL of 30% v/v piperidine in DMF, and shaken for 2 hours to cleave the Fmoc protecting group. After filtration, the resin was subjected to the usual wash and dry cycle; the resin weighed 1.588 g.
  • the resin, acetic anhydride (591 mg, 5.8 mmol) and DIEA (748 mg, 5.8 mmol) were taken in 15 mL of meth ylene chloride and shaken overnight to acetylate at N 1 . After filtration, the resin was washed with methylene chloride and dried in a vacuum desiccator for 5 hours. The resin was shaken with 15 mL of 1 : 1 TFA:methylene chloride for 1 hour to cleave the tBoc protecting group at N 4 .
  • the resin was washed with methylene chloride (5x15 mL), followed by 20% triethyl amine in methylene chloride (5x15 mL) and then again with methylene chloride (5x15 mL). After drying, the resin weighed 1.294 g. 669 Mg of the resin from the previous step, DIEA (116 mg., 0.9 mmol) and 4-chloro-2-(1-imidazolyl)-6-isopropylpyrimidine (200 mg, 0.9 mmol) were taken up in 6 mL of DMF and heated to 80°C for 24 hours. After filtration the resin was washed (DMF, methanol and methylene chloride) and dried.
  • DIEA 116 mg., 0.9 mmol
  • 4-chloro-2-(1-imidazolyl)-6-isopropylpyrimidine 200 mg, 0.9 mmol
  • ["R” is H or alkyl; "B” is O or NH; X is an electron withdrawing group such as Br, Cl, or I;

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DE69836422T2 (de) 2007-06-14
EP0968206B1 (fr) 2006-11-15
EP1754703A2 (fr) 2007-02-21
KR20000075615A (ko) 2000-12-26
EP0968206A1 (fr) 2000-01-05
EP1754703A3 (fr) 2007-02-28
JP4495257B2 (ja) 2010-06-30
HK1025952A1 (en) 2000-12-01
CN1252799A (zh) 2000-05-10
DE69836422D1 (de) 2006-12-28
NO321664B1 (no) 2006-06-19
IL131475A0 (en) 2001-01-28
ES2277382T3 (es) 2007-07-01
NO993996D0 (no) 1999-08-19
ATE345339T1 (de) 2006-12-15
CA2281545A1 (fr) 1998-08-27
GB2338957A8 (en) 2000-01-26
SK286779B6 (sk) 2009-05-07
AU6174998A (en) 1998-09-09
AU732969B2 (en) 2001-05-03
DK0968206T3 (da) 2007-03-26
CA2281545C (fr) 2007-04-24
PL335235A1 (en) 2000-04-10
NO993996L (no) 1999-10-18
JP2002515058A (ja) 2002-05-21
RU2241708C2 (ru) 2004-12-10
GB9919686D0 (en) 1999-10-20
PT968206E (pt) 2007-02-28
NZ337861A (en) 2001-02-23
CN1100777C (zh) 2003-02-05
WO1998037079A1 (fr) 1998-08-27
CZ2008628A3 (cs) 2016-09-29
GB2338957B (en) 2001-08-01
SK113599A3 (en) 2000-07-11

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